Our understanding of the molecular biology of cancer has improved dramatically over the past thirty years, and many potential therapeutic agents have been developed. However a way to realize the full clinical potential of these agents has yet to be found. Our hypothesis is that a therapeutic agent must satisfy two requirements to be effective: (1) the agent must be delivered to the target cells in vivo in optimal quantities, remaining there for an appropriate time at sufficient concentrations, and (2) the agent must be effective in the in vivo microenvironment of primary and metastatic tumors. We also hypothesize that creative manipulation of the tumor microenvironment will significantly improve the delivery and effectiveness of many types of therapeutic agents. This Program Project Grant (PPG) application builds on these premises. Our primary objective is to develop a quantitative understanding of the physiological barriers to the delivery and effectiveness of conventional and novel therapeutic agents used for solid tumor treatment. Our secondary objective is to seek strategies with the potential to overcome these barriers. One of the strengths of our PPG is development and utilization of state-of-the-art optical imaging techniques. However, due to rapid progress and unusually high productivity of all projects of this PPG (as documented by publications in journals such as Science, Nature, Nature Medicine, Nature Reviews Cancer, PNA5 and Circulation Research in the past 12 months), demand for our high resolution in vivo, ex vivo, and in vitro imaging has significantly increased. Therefore, the availability of these imaging resources has become a limiting factor in our effort to continue to make progress. In this Supplement request, we propose to obtain 1) a Multi-photon Laser Scanning Microscope Work Station to be housed within our gnotobiotic animal facility for in vivo imaging of regions deep inside tumors, and 2) a Confocal Laser Scanning Microscope Work Station which will be located outside the animal facility for high resolution ex vivo and in vitro imaging. The new systems will fill the urgent need to image specific molecular, cellular, anatomical and functional parameters in normal and tumor tissues in mice during tumor growth, regression, relapse and metastasis, and will make these novel imaging resources available to all projects in our PPG. This equipment will also fill the critical needs of our NCI supported Bioengineering Research Partnership Grant, R24 CA-85146. The proposed imaging equipment, in combination with our expertise in biomedical engineering and cancer research, will provide the power to uncover molecular mechanisms of blood and lymph angiogenesis, as well as the invasion and metastasis of tumors. Interdisciplinary research, our major strength, will be further enhanced by complementary functional imaging and common image analysis approaches enabled with this Supplement. [unreadable] [unreadable] [unreadable] COLLABORATING INSTITUTION (S): None [unreadable] [unreadable] [unreadable] PROGRESS IN THE CURRENT FUNDING PERIOD: During the current funding period, Dr. Jain and his colleagues have published 44 original articles and 15 reviews that are attributed to the program project grant CA080124. There are 15 publications and 6 abstracts attributed to the R24 CA085146 grant. This clearly demonstrates that the investigators are active, productive scientists whose work is accepted by top-level journals, and that research progress is progressing well. [unreadable] [unreadable] [unreadable]